Abstract
Aromatic amines (AAs) are chemicals of industrial, pharmacological and environmental relevance. Certain AAs, such as 4-aminobiphenyl (4-ABP), are human carcinogens that require enzymatic metabolic activation to reactive chemicals to form genotoxic DNA adducts. Arylamine N-acetyltransferases (NAT) are xenobiotic metabolizing enzymes (XME) that play a major role in this carcinogenic bioactivation process. Isothiocyanates (ITCs), including benzyl-ITC (BITC) and phenethyl-ITC (PEITC), are phytochemicals known to have chemopreventive activity against several aromatic carcinogens. In particular, ITCs have been shown to modify the bioactivation and subsequent mutagenicity of carcinogenic AA chemicals such as 4-ABP. However, the molecular and biochemical mechanisms by which these phytochemicals may modulate AA carcinogens bioactivation and AA-DNA damage remains poorly understood.This manuscript provides evidence indicating that ITCs can decrease the metabolic activation of carcinogenic AAs via the irreversible inhibition of NAT enzymes and subsequent alteration of the acetylation of AAs. We demonstrate that BITC and PEITC react with NAT1 and inhibit readily its acetyltransferase activity (ki = 200 M−1.s−1 and 66 M−1.s−1 for BITC and PEITC, respectively). Chemical labeling, docking approaches and substrate protection assays indicated that inhibition of the acetylation of AAs by NAT1 was due to the chemical modification of the enzyme active site cysteine. Moreover, analyses of AAs acetylation and DNA adducts in cells showed that BITC was able to modulate the endogenous acetylation and bioactivation of 4-ABP. In conclusion, we show that direct inhibition of NAT enzymes may be an important mechanism by which ITCs exert their chemopreventive activity towards AA chemicals.
Highlights
Aromatic amines (AAs) represent one of the most important class of industrial and environmental chemicals [1, 2]
The cancer chemopreventive activity of ITCs is attributed, at least in part, to their ability to alter the metabolic activation of procarcinogens through inhibition of cytochromes P450 (CYP450) enzymes and nuclear factor E2-related factor (Nrf2)-dependent induction of phase II xenobiotic metabolizing enzymes (XME), such as glutathione S-transferase (GST) enzymes [12,13,14]
Given the key role of NATs in the metabolic activation of AA carcinogens, we hypothesized that these enzymes could be targeted by chemopreventive ITCs such as BITC or PEITC (Figure 1A)
Summary
Aromatic amines (AAs) represent one of the most important class of industrial and environmental chemicals [1, 2]. Cellular metabolic activation of procarcinogenic AAs relies on their N-hydroxylation by CYP450 (such as CYP1A1, 1A2 or 2E1), and further activation by NAT-catalyzed O-acetylation This step results in acetoxy ester metabolites that spontaneously degrade to form arylnitrenium ions that can form bulky adducts on DNA leading to the production of mutations [1, 4]. The cancer chemopreventive activity of ITCs is attributed, at least in part, to their ability to alter the metabolic activation of procarcinogens through inhibition of CYP450 enzymes and nuclear factor E2-related factor (Nrf2)-dependent induction of phase II XME, such as glutathione S-transferase (GST) enzymes [12,13,14]. Alteration of the NAT-dependent metabolism of AAs by ITCs may represent a novel biochemical mechanism by which these phytochemicals exert their chemoprotective effects towards AA carcinogens
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